PROJECT SUMMARY In 2014, an estimated 70,800 people in the US will be diagnosed with non-Hodgkin lymphoma (NHL), and 18,990 will die from this cancer. NHL incidence rates increased over the last half of the 20th century and only recently stabilized. In parallel, NHL survival rates began improving in the mid-1990s with the advent of improved treatment strategies, leading to the current 5-year survival rate of 69%. These trends have led to a growth in the number of NHL survivors, estimated at over 650,000 in 2010. To address the current and long-term unmet health needs of this growing patient population, we propose to establish the Lymphoma Epidemiology of Outcomes (LEO) cohort study, which will expand an ongoing cohort of over 4,000 NHL patients that was established in 2002. The goal of expanding this infrastructure to over 12,000 NHL patients is to support a broad research agenda aimed at identifying novel clinical, epidemiologic, host genetic, tumor, and treatment factors that significantly influence NHL prognosis and survivorship. To meet these goals, over the next 5 years we propose to: 1) Expand recruitment to six new centers, with a goal of recruiting 8,700 newly diagnosed NHL patients (including 1,000 African American and 1,400 Hispanic participants), for a total cohort of 12,900 patients (including 3,700 diffuse large B-cell and 3,300 follicular lymphomas); 2) Review all pathology diagnoses and build a NHL tumor bank that includes an H&E slide, a formalin-fixed, paraffin-embedded tissue samples, and extracted tumor DNA and RNA; 3) Collect a peripheral blood sample and bank DNA, serum, plasma and buffy coat in a central biorepository; 4) Annotate and harmonize all cases with clinical, epidemiologic, pathology and treatment data; 5) Prospectively follow patients in the cohort regularly to ascertain disease progression/relapse, retreatment, transformation, second cancers, survival (including cause of death), updated exposures, patient-reported outcomes (PROs), and other long-term health outcomes; and 6) Facilitate research projects that use this infrastructure and promote interactions with lymphoma clinical trial networks. We will achieve these aims through close coordination of each of the participating centers, supported by four cores (Administration; Clinical; Pathology & Biospecimens; and Biostatistics & Informatics). These cores will also conduct methodological research to enhance data collection, patient follow-up, biospecimen science and statistical modeling. The proposed LEO cohort infrastructure overcomes limitations of other study designs, is feasible, and will be used to improve diagnosis, risk stratification, treatment, and short and long-term management of NHL patients. The LEO investigators will leverage this resource to foster discovery and validation of novel biologic and clinical insights. LEO will be led by international leaders in clinical and epidemiologic research on NHL thereby driving the translation of new findings to the clinic and the population.